title: A GDF5 point mutation strikes twice--causing BDA1 and SYNS2.
abstract: Growth and Differentiation Factor 5 (GDF5) is a secreted growth factor that belongs to the Bone Morphogenetic Protein (BMP) family and plays a pivotal role during limb development. GDF5 is a susceptibility gene for osteoarthritis (OA) and mutations in GDF5 are associated with a wide variety of skeletal malformations ranging from complex syndromes such as acromesomelic chondrodysplasias to isolated forms of brachydactylies or multiple synostoses syndrome 2 (SYNS2). Here, we report on a family with an autosomal dominant inherited combination of SYNS2 and additional brachydactyly type A1 (BDA1) caused by a single point mutation in GDF5 (p.W414R). Functional studies, including chondrogenesis assays with primary mesenchymal cells, luciferase reporter gene assays and Surface Plasmon Resonance analysis, of the GDF5(W414R) variant in comparison to other GDF5 mutations associated with isolated BDA1 (p.R399C) or SYNS2 (p.E491K) revealed a dual pathomechanism characterized by a gain- and loss-of-function at the same time. On the one hand insensitivity to the main GDF5 antagonist NOGGIN (NOG) leads to a GDF5 gain of function and subsequent SYNS2 phenotype. Whereas on the other hand, a reduced signaling activity, specifically via the BMP receptor type IA (BMPR1A), is likely responsible for the BDA1 phenotype. These results demonstrate that one mutation in the overlapping interface of antagonist and receptor binding site in GDF5 can lead to a GDF5 variant with pathophysiological relevance for both, BDA1 and SYNS2 development. Consequently, our study assembles another part of the molecular puzzle of how loss and gain of function mutations in GDF5 affect bone development in hands and feet resulting in specific types of brachydactyly and SYNS2. These novel insights into the biology of GDF5 might also provide further clues on the pathophysiology of OA.
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, Berlin, Germany ; Berlin-Brandenburg School for Regenerative Therapies (BSRT), Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Elisa
authors.initials: E
authors.lastname: Degenkolbe
authors.forename: Jana
authors.initials: J
authors.lastname: König
authors.forename: Julia
authors.initials: J
authors.lastname: Zimmer
authors.forename: Maria
authors.initials: M
authors.lastname: Walther
authors.forename: Carsten
authors.initials: C
authors.lastname: Reißner
authors.forename: Joachim
authors.initials: J
authors.lastname: Nickel
authors.forename: Frank
authors.initials: F
authors.lastname: Plöger
authors.forename: Jelena
authors.initials: J
authors.lastname: Raspopovic
authors.forename: James
authors.initials: J
authors.lastname: Sharpe
authors.forename: Katarina
authors.initials: K
authors.lastname: Dathe
authors.forename: Jacqueline T
authors.initials: JT
authors.lastname: Hecht
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.forename: Sandra C
authors.initials: SC
authors.lastname: Doelken
authors.forename: Petra
authors.initials: P
authors.lastname: Seemann
mesh_terms: D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D059327:Brachydactyly / Q000235:genetics* / Q000503:physiopathology; D002645:Chickens; D055428:Growth Differentiation Factor 5 / Q000235:genetics*; D006801:Humans; D051379:Mice; D010003:Osteoarthritis / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics; D011485:Protein Binding; D015398:Signal Transduction; D013580:Synostosis / Q000235:genetics* / Q000503:physiopathology
chemical_list: D019485:Bone Morphogenetic Proteins; C525893:GDF5 protein, human; D055428:Growth Differentiation Factor 5; C498211:BMPR1A protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I